Derivatives of 1H-imidazo{8 4,5-c{9 pyridine-7-carboxylic acids and esters

ABSTRACT

New derivatives of 1H-imidazo(4,5-c)pyridine-7-carboxylic acids and esters and their acid addition salts having the general formula   ARE DISCLOSED. They are useful as anti-inflammatory agents and central nervous system depressants. In addition, this type of compound increases the intracellular concentration of adenosine3&#39;&#39;,5&#39;&#39;-cyclic monophosphate.

United States Patent [1 1 Denzel et a].

[ June 24, 1975 1 DERIVATIVES OF 1H-IMIDAZO[4,5-C]PYRIDINE-7- CARBOXYLICACIDS AND ESTERS {75} Inventors: Theodor Denzel. Regensburg; Hans Hoehn,Tegernheim. both of Germany [73] Assignee: E. R. Squibb & Sons. lnc.,

Princeton. NJ.

221 Filed: Feb. 7, 1974 1211 Appl. NO.1440,620

[52] US. Cl 260/2955 B; 424/266; 260/240 G;

OTHER PUBLICATIONS Chemical Abstracts. Vol. 44. Colsv 5361 to 5362(1950). Chemical Abstracts. Vol. 44.011 7353 (1950). (abst. of BritishPatent 629.441 Mutsushima et a1. Chem. Pharm. Bull. 1968. Vol. 16. pp.2277 to 2282.

Chemical Abstracts, Vol. 72, Abst. No. 12687 (1970) (abst. of De R00 eta1.)

Chemical Abstracts. Vol. 78. Abst. No. 83672 e (April 1973).

Primary E.\'aminerJohn D. Randolph Attorney. Agent. or FirmLawrence S.Levinson'. Merle J. Smith; Stephen B. Davis [57] ABSTRACT Newderivatives of lH-imidaz0[4.5-c]pyridine-7 carboxylic acids and estersand their acid addition salts having the general formula are disclosed.They are useful as anti-inflammatory agents and central nervous systemdepressants. In ad dition. this type of compound increases theintracellu- Iar concentration of udenosine-3'.5 '-cyclic monophosphate.

15 Claims, N0 Drawings DERIVATIVES OFlH-IMIDAZO(4,S-C)PYRIDINE-7-CARBOXYLIC ACIDS AND ESTERS SUMMARY OF THEINVENTION This invention relates to new derivatives of 1H-imidazol4,5-c}pyridine-7-carboxylic acids and esters and acid additionsalts thereof having the general formula The symbols have the followingmeaning in formula wherein R and R are hydrogen or lower alkyl, ahydrazine wherein R R,,, and R are each independently selected fromhydrogen, lower alkyl, and phenyl, and R is lower alkyl or phenyl.

R is hydrogen, lower alkyl, or phenyl.

The lower alkyl group referred to throughout this specification includestraight or branched chain hydrocarbon groups containing 1 to 7 carbonatoms, preferably l to 4 carbons. Examples of the type of groupscontemplated are methyl, ethyl, propyl, isopropyl, etc. The lower alkoxygroups include such lower alkyl groups bonded to an oxygen, e.g.,methoxy, ethoxy, propoxy, isopropoxy, etc. The phenyl-lower alkyl groupsinclude such lower alkyl groups bonded to a phenyl, e.g., benzyl,phenethyl, etc.

The substituted phenyl groups include one or two simple substituents,i.e., lower alkyl, lower alkoxy, halogen (F, Cl, Br, or I, preferably Clor Br), CF amino or carboxy. Examples of the type of groups contemplatedare 0-, m-, or p-chlorophenyl, 0-, mor p-tolyl, 2,5-dichlorophenyl,3,5-dimethylphenyl, 3,4- dimethoxyphenyl, 0-, mor p-chlorobenzyl, 3,5-dichlorophenethyl, etc.

Preferred embodiments of this invention are as follows:

R is hydrogen or lower alkyl of l to 4 carbons, especially ethyl.

R is hydrogen or lower alkyl of l to 4 carbons, especially ethyl orbutyl.

R is hydrogen or lower alkyl of l to 4 carbons, especially hydrogen ormethyl.

R is lower alkoxy of l to 4 carbons, especially ethoxy, amino, loweralkylamino of l to 4 carbons, especially ethyl or butylamino,

where R is hydrogen and R is hydrogen or lower alkyl of l to 4 carbons,especially where both R, and R are hydrogen, or

where R and R are both lower alkyl of l to 4 carbons, especially where Rand R are both methyl.

R is hydrogen or lower alkyl of l to 4 carbons, especially methyl.

DETAILED DESCRIPTION The new compounds of formula I are formed by thefollowing series of reactions. The symbols in the structural formulashave the same meaning as previously described.

A 4,6-dihydroxypyridine carboxylic acid ester of the formula a (II) o NCOOR HO/ \b(\\ R4 (produced analogs to the procedure described in Chem.Ber. 99, 244, (1966)), is reacted with an inorganic acid chloride suchas phosphorous oxychloride,

with chlorine atoms in the 2 and 4 position of the molecule.

This compound is now treated in a solvent such as alcohol with theappropriate amine of the formula at about C in the presence ofa basesuch as triethylamine. By this reaction a product of formula 3 4 (V) HWRor with a carboxylic acid of formula 1 m l (x) n coon (J) Compounds offormula Um R is obtained. l R

Treatment of compounds of formula V with appro- R i r \V/ 2 i te ami esoff I 4 r a n ormu p a m; n

i (VI) R o 5 a lkyl R6 IS with an alkoxy group are now produced byreacting compounds of formula V with an alkali metal alcoholate. By thisprocedure a compound of formula in the presence of a base such astriethylamine produces a compound of formula a].kylO R4 which is nowhydrogenated catalytically with a catalyst such as palladium or nickelor by a reduction with a metal-acid pair such as zinc in acetic acid,iron in hydrochloric acid or the like, producing a tri-amino compound offormula is produced with an alkoxy group in the 6-position of themolecule. v This compound is processed as described above, e.g.,reduction of the nitro group either catalytically or with a metal-acidpair such as zinc in acetic acid. This results (in in formation ofcompounds of formula H N v 0x11. (XII) g l 40 HNR 5 N 'I;I R l 4 HZNCOOR O alkyl-O u R Compounds of formula which are now treated with orthocarboxylic acid ester (1 a) or carboxylic acid of formulas IX or X togive products of formula lb.

Compounds of formula la are alternatively produced by a reaction ofcompounds of formula lb with an appropriate amine of formula VI.

Compounds of formula it OR (1c) 0 4\ Y 2 l O l with an amino group arenow obtained by reaction of N -N compounds of formula Vlll with an orthocarboxylic acid ester of the formula (IX) O-alkyl ,5

with a hydrazino group, are formed by reaction of compounds of formulalb with the corresponding hydrazine O-alkyl of the formula with ahydrazone group are obtained by reaction of compounds of formula lc withaldehydes or ketones of formula (XIV) The bases of formula l formpharmaceutically acceptable acid addition salts by reaction withequivalent amounts of the common inorganic and organic acids. Such saltsinclude the hydrohalides, e.g., hydrobromide, hydrochloride, sulfate,nitrate, phosphate, acetate, citrate oxalate, tartrate, malate,succinate, benzoate, ascorbate, alkanesulfonate, e.g., methanesulfonate,arylsulfonate, e.g., benzenesulfonate, etc. It is frequently convenientto purify or isolate the product by forming an insoluble salt. The basemay be obtained by neutralization and another salt then formed bytreatment with the appropriate acid.

The new compounds of this invention and their acid addition salts haveanti-inflammatory properties and are useful as anti-inflammatory agents,for example, to reduce local inflammatory conditions such as those of anedematous nature or resulting from proliferation of connective tissue invarious mammalian species such as rats, dogs and the like when givenorally in dosages of about to 50 mg/kg/day, preferably 5 to 25mg/kg/day, in single or 2 to 4 divided doses, as indicated by thecarageenan edema assay in rats. The active substance may be utilized incompositions such as tablets, capsules, solutions or suspensionscontaining up to about 300 mg. per unit of dosage of a compound ormixture of compounds of formula I. They may be compounded inconventional manner with a physiologically acceptable vehicle orcarrier, excipient, binder, preservative, stabilizer, flavor, etc. ascalled for by accepted pharmaceutical practice. Topical preparationscontaining about 0.01 to 3 percent by weight of active substance in alotion, salve or cream may also be used.

The new compounds of this invention and their acid addition salts alsohave central nervous system depressant activity and can be used astranquilizers or ataractic agents for the relief of anxiety and tensionstates, for example, in mice, cats. rats, dogs and other mammalianspecies, in the same manner as chlordiazepoxide. For this purpose acompound or mixture of compounds of formula I or formula II or theiracid addition salts is administered orally or parenterally in aconventional dosage form such as tablet, capsule, injectable or thelike. A single does, or preferably 2 to 4 divided daily doses, providedon a basis of about I to mg. per kilogram per day, preferably about 2 to15 mg. per kilogram per day is appropriate. These may be conventionallyformulated in an oral or parenteral dosage form by compounding about l0to 250 mg. per unit dosage with conventional vehicle, excipient, binder,preservative, stabilizer, flavor or the like as called for by acceptedpharmaceutical practice.

The new compounds and their acid addition salts also increase theintracellular concentration of adenosine- 3',5'-cyclic monophosphate,and thus by the administration of about 1 to 100 mg. per kilogram perday, preferably about 10 to 50 mg. per kilogram, in single or 2 to 4divided doses in conventional oral or parenteral dosage forms such asthose described above may be used to alleviate the symptoms of asthma.

The following examples are illustrative of the invention. Alltemperatures are on the Centigrade scale.

EXAMPLE 1 4-Amino-l-butyl-6-methyl-lH-imidazo[4,5-clpyridine-7-carboxylic acid ethyl ester.

a. 4,6-Dichloro'2-methyl-S-nitro-pyridine-3-carboxylic acid ethyl ester242 g. of 4,6-dihydroxy-2-methyl-5-nitro-pyridine-3- carboxylic acidethyl ester l Mol.) are heated at 120 with 500 ml. phosphorousoxychloride for 3 hours. After this time, the excess phosphorousoxychloride is removed in vacuo and the black residue decomposed bypouring into ice-water. About 1 liter of chloroform is added and themixture is filtered to remove undis solved material. The organic layeris separated and the aqueous phase extracted twice with 100 ml. portionsof chloroform. The extract is dried over calcium chloride, filtered andevaporated to dryness. The resulting oil is crystallized with about 500ml. benzene, yielding 153 g. of4,6-dichloro-2-methyl-5-nitro-pyridine-3- carboxylic acid ethyl ester mp4546. b. 4-Butylamino-6-chloro-2-methyl-5-nitro-pyridine-3- carboxylicacid ethyl ester 139.5 g. of the4,6-dichloro-2-methyl-S-nitropyridine-3-carboxylic acid ethyl ester (0.5Mol.) are dissolved in about 500 ml. methanol. g. of triethylamine areadded and the solution is heated at reflux temperature. At this point,36.5 g. of n-butylamine are added dropwise. This process should becompleted in about 2 hours. The solvent is then removed in vacuo and 500ml. benzene are added to the residue. The triethylamine hydrochloride isremoved by filtration and the solvent evaporated. The resulting oil isdissolved in 300 ml. methanol and yields on cooling 110 g. 4-butylamino-6-chloro-2-methyl-S-nitro-pyridine-3- carboxylic acid ethylester mp. 3536 (methanol). c.6-Amino-4-butylamino-2-methyl-5-nitro-pyridine-3- carboxylic acid ethylester 177.9 g. of4-butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethylester (0.5 Mol.) and 500 ml. of ethanol are heated in an autoclavetogether with 300 ml. aqueous ammonia (30% at about 60 for 10 hours.After this time, the solvent is distilled off and the residue of6-amino-4-butylamino-2-methyl-5-nitro- 7 pyridineJ-carboxylic acid ethylester recrystallized. from methanol. Yield is 135 g. (91%); m.p. 9899.d. 5,6-Diamino-4-butylamino-Z-methyl-pyridine-3- carboxylic acid ethylester 29.6 g. of 6-amino-4-butylamino-2-methyI-pyridine- 3-carboxylicacid ethyl ester (0.1 Mol.) are dissolved in 150 ml. acetic acid. Thesolution is heated at reflux temperature. Zinc is added carefully untilthe solution is colorless (about 20 g.) and heating is continued for anadditional 10 minutes. The mixture is evaporated to dryness and about lml. of water are added. The solution is neutralized with dilute aqueousammonia and extracted three times with l00 ml. portions of ether. Theether extracts are combined, dried with calcium chloride and the solventevaporated. The oily residue of5,6-diamino-4-butylamino-2-methyl-pyridine'3- carboxylic acid ethylester crystallizes with methanol. Yield is 21 g. (79%); m.p. 8283(methanol/H O). e. 4-Amin0-l-butyl-6-methyl-lH-imidazo[4,5-

clpyridine-7carboxylic acid ethyl ester.

26.6 g. of 5,6-diamino-4-butylamino-2-methylpyridine-B-carboxylic acidethyl ester are refluxed in 100 ml. formic acid for 6 hours. After theexcess of formic acid is removed in vacuo, 4-amino-l-butyl-6-methyl-lH-imidazo[4,5-c]pyridine-7 carboxylic acid ethyl estercrystallizes. Yield is 20.5 g. (74%); m.p. l33-l34C (methanol).

EXAMPLE 2 l-Ethyl-4-(ethylamino)-6-methyl-lH-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester.

4,6-Di(ethylamino)-2-methyl-5-nitro-pyridine-3- carboxylic acid ethylester. 27.9 g. of 4,6-dichloro-2-methyl-5-nitro-pyridine-3- carboxylicacid ethyl ester (0.1 Mol. of example la are dissolved in 200 ml.methanol. The solution is heated at reflux temperature and a solution of22.5 g. ethylamine (0.5 Mol.) in 50 ml. methanol is added dropwise.After the addition is completed, the solvent is distilled off and theresidue extracted with about 300 ml. benzene. The benzene is removed andthe residue of 4,6- di-ethylamino-Z-methyl--nitro-3-pyridine-carboxylicacid ethyl ester recrystallized from methanol. Yield is 22.5 g. (76%);m.p. 6365. b. 5-Amino-4,6-di-ethylamino-6-methyl-pyridine-3- carboxylicacid ethyl ester.

29.6 g. of 4,6-di-ethylamino-2-methyl-5-nitropyridine-3-carboxylic acidethyl ester are dissolved in 100 ml. of butyl alcohol, 0.2 g. palladiumon charcoal are added and the solution is hydrogenated in an autoclaveat 60 and l0 atm. pressure. Filtration of the catalyst and evaporationof the solvent yields 26 g. of oily5-amino-4,6-di-ethylamino-6-methyl-pyridine-3- carboxylic acid ethylester. (98%).

c. lEthyl-4-(ethylamino)-6-methyl-lH-imidazo[4.5-

cjpyridine-7-carboxylic acid ethyl ester.

26.6 g. of 5-Amino-4,6-di(ethylamino)-2-methylpyridine-3-carboxylic acidethyl ester and 100 ml. of formic acid are refluxed for 5 hours.Evaporation of formic acid yields crystalline l-ethyl-4-( ethylamino)-6-methyl- H-imidazo-[4.5-c ]pyridine-7-carboxylic acid ethyl ester. Yieldis 18.2 g. (62%); m.p. 63-65 (ligroin).

EXAMPLE 3 1 -Butyl-4-(ethylamino)-6-methyl-lH-imidazo[4,5-clpyridine-7-carboxylic acid ethyl ester.

a. 4-butylamino-6-ethylamino-l2-methyl-5-nitrorpyridine-3-carboxylicacid ethyl ester. When4-butylamino-6-chloro-2-methyl-5-nitropyridine3-carboxylic acid ethylester of example 1b is treated with ethylarnine according to theprocedure of example 1c, 4-butylamino-6-ethylamino-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester is obtained in an 83%yield; m.p. 5355.

b. 5-Amino-4-butylamino-6-ethylamino-2-methylpyridine-3-carboxylic acidethyl ester. Hydrogenation of 4-butylamino-6-ethylamino-2-methyl-S-nitro-pyridine-3-carboxylic acid ethyl ester according to theprocedure of example 1d results in formation of oily5-amino-4-butylamino-6 ethylamino-2- methyl-pyridine-3-carboxylic acidethyl ester. Yield is c. l-Butyl-4-(ethylamino)-6-methyl-lH-imidazo[4,5-

clpyridine-7-carboxylic acid ethyl ester.

25.4 g. of 5-Amino-4-butylamino-6-ethylamino-2-methylpyridine-3-carboxylic acid ethyl ester and g. of ortho-formic acidethyl ester are refluxed for 12 hours. The excess ortho ester is removedin vacuo and the oily residue distilled. B.p. 0.1 200-2l5. The fractioncrystallizes on the addition of 50 ml. of a 1:1 mix ture ofpetrolether/ether. l-Butyl-4-(ethylamino)-6- methyl- 1 H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester is recrystallized frompetrolether. Yield is l8 g. (59%); m.p. 46-48.

EXAMPLE 4 4-(Butylamin0)-l-ethyl-2,6-dimethyl-lH-imidazo[4,5-clpyridine-7-carboxylic acid ethyl ester.

a. 6-Chloro-4-ethylamino-2-methyl-5-nitro-pyridine-3- carboxylic acidethyl ester.

When 4,6-dichloro-2-methyl-pyridine-3-carboxylic acid ethyl ester ofexample la is treated with ethylamine according to the procedure ofexample lb, 6- chloro-4-ethylamino-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester is obtained. Yield is 69%; m.p. 36-37(methanol).

b. 6-Butylamino-4-ethylamino-2-methyl-S-nitropyridine-3-carboxylic acidethyl ester.

Treatment of 6-chloro-4-ethylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester with nbutylamine accordingto the procedure of example lc,6-butylamino-4-ethylamino-2-methyl-5-nitro-pyridine- 3-carboxylic acidethyl ester is formed. Yield is 88%; m.p. 40-42 (methanol).

c. 5-Amino-6-butylamino4-ethylamino-2-methylpyridine 3 carboxylic acidethyl ester. Hydrogenation of 6-butylamino-4-ethylamino-2-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester according to theprocedure of example 2b yields 5-amino-6-butylamino-4-ethylamino-2-methyl-pyridine- 3-carboxylic acidethyl ester. Yield is 96%.

d. 4-( Butylamino l -ethyl-2 ,6-dimethyl l H-imidazol4,5-cl-pyridine-7-carboxylic acid ethyl ester.

When 5-Amino-4-butylamino-6-ethylamino-2- methylpyridine-3-carboxylicacid ethyl ester is treated with ortho acetic acid ethyl ester accordingto the procedure of example 30. 4-(butylamino)-l-ethyl-2,6- dimethyllH-imidazo-l 4,5-c ]pyridine-7-carboxylic 9 acid ethyl ester is obtained.Yield is 55%. B.p. 0.1

l95-2l5; m.p. 44-46.

EXAMPLE l-Ethyl-4-ethylamino-2,6-dimethyll H-imidazo[4,5-cl-pyridine-7-carboxylic acid ethyl ester.

When 5-Amino-4,6-di-ethylamino-6-methylpyridine-3-carboxylic acid ethylester of example 2b is yields 125 g. (90%) of oily5-amino-4-ethylamino-6- ethoxy-2-methyl-pyridine-3-carboxylic acid ethylester. c. l-Ethyl-4-ethoxy-6-methyl-lH-imidazo{4,5-

c]pyridine-7-carboxylic acid ethyl ester.

26.7 g. of 5-Amino-4-ethylamino-6-eth0xy-2- methylpyridine3-carboxylicacid ethyl ester (0.] Mol.) and 100 ml. of orthoformic acid ethyl esterare refluxed for 10 hours. The excess of orthoester is distilled off andthe residue of l-ethyl-4-ethoxy--methyl-lH- "ealed with 0mm acetic acidethyl ester according to 10 imidazo[4,5-clpyridine-7-carboxylic acidethyl ester is the procedure of example 3c. l-ethyl-4-ethylamino-2.6-dimethyll H-imidazo-l4,5-clpyridine-7-carboxylic acid ethyl ester isobtained. Yield is 58%; B.p. l90-220 m.p. 3638 (petrolether/ether).

EXAMPLE 6 4-Butylamino-l-ethyl-6-methyl-lH-imidazo[4,5-e]pyridine-7-carboxylic acid ethyl ester.

5-Amino-6-butylamino-4-ethylamino-Z-methylpyridine-3-carboxylic acidethyl ester of example 4c is treated with formic acid according to theprocedure of example to give 4-butylamino-l-ethyl-6-methyl-IH-imidazo[4,5-clpyridine-7-carboxylic acid ethyl ester. Yield is 55 /1;B.p. l90-2l0; m.p. 34-36 (Petrolether/ether).

EXAMPLE 7 l-Ethyl-4-ethoxy-o-methyll H-imidazo[4,5-clpyridine-7-carboxylic acid ethyl ester.

a. 4-Ethylamino-o-ethoxy-5-nitro-2-methyl-pyridine-3- carboxylic acidethyl ester.

287 g. of 6-Chloro-4-ethylamino-5-nitro-6-methylpyridine-3-carboxylicacid ethyl ester (1 Mol.) of example 4a are slowly added to a gentlyrefluxing mixture of 24 g. of sodium in 750 ml. of dry alcohol. Themixture is heated with stirring for an additional hour. After cooling toroom temperature, the sodium chloride is filtered off and the filtrateevaporated to dryness. The oily residue of4-ethylamino-6-ethoxy-5-nitro-2- methyl-pyridine-3-carboxylic acid ethylester is crystallized with methanol. Yield is 305 g. (82%); m.p. 4042(methanol).

b. 5-Amino-4-ethylamino-6-ethoxy-2-methyl-pyridine- 3-carboxylic acidethyl ester.

[66 g. of 4-Ethylamino-6-ethoxy-5-nitro-2-methyl pyridine-B-carboxylicacid ethyl ester (0.5 M01.) are dissolved in 600 ml. of butanol andhydrogenated acrecrystallized from petrol ether. Yield is 18.2 g. mp.45-46.

EXAMPLE 8 l-Ethyl-6-rnethyl-4-[2-( l-methylethylidene )hydrazino1- lH-imidazo[4,5-c]pyridine-7- carboxylic acid ethyl ester.

3. l-Ethyl-4-hydrazino-6-methyl-l H-imidazo[4,5-

clpyridine-7-carboxylic acid ethyl ester.

2.8 g. of l-Ethyl-4-ethoxy-6-methyl-lH-imidazo{4,5-cl-pyridine-7-carboxylic acid ethyl ester (0.01 Mol.) andn l g. ofhydrazine hydrate are refluxed in about 1 ml. butyl alcohol for 10hours. After this time, the mixture is evaporated to dryness and theremaining lethyl-4-hydrazino-6-methyll H-imidazo[4,5-clpyridine-7-carboxylic acid ethyl ester recrystallized from methanol.Yield is l.9 g. (73%); m.p. l20122. b. l-Ethyl-6-methyl-4[2-(l-methylethylidene)hydrazino]-1H-imidazo[4,5-clpyridine- 7-carboxylicacid ethyl ester.

2.6 g. of l-Ethyl-4-hydrazino-6-methyl-lH-imidazo-[4,5-c]pyridine-7-carboxylic acid ethyl ester (0.0l Mol.) are dissolvedin l0 ml. acetone. The mixture is allowed to stand overnight at roomtemperature. The excess of acetone is distilled off and the crystallineresidue of l-ethyl-6-methyl-4-[ 2-(l-methylethylidene)hydrazino]-lH-imidazo[4,5-c]-pyridine-7- carboxylicacid ethyl ester recrystallizes from ethylacetate. Yield is 2.9 g. m.p.l5l153.

EXAMPLES 9-41 Following the procedure of example l but employing theappropriate 2-substituted-4,fi-dihydroxypyridine carboxylic acid orester of formula II and the appropriate amine of formula IV results inthe production of various tri-amino compounds of formula Vlll which whenreacted with the appropriate ortho carboxylic acid ester of formula [Xyields the products of formula cording to the procedure described inexample 2b. This 50 la.

c 0. l u) C 11 l l 4 .21 R i u r Z r f l;

E: R l R P 9 H H CH ca 10 on P n (unlinued CII.

-(ontinued R R1 R2 I;

29 c 11 CH2@-F H cH 30 c 5 CH2- C: -CF3 H CH3 31 c 13 CH2CO0H H CH3 32 c13 -CH2-CH2-@-C2H5 H CH3 a; 33 c 13 -cH -cH -(6\ H CH3 ocn 34 0 13CH2-CH2@ H ch 35 (2 11 CH2C1I2 -NH2 H ca 36 c 33 c 23 c 13 z 37 c n c 30 13 C13 38 c n C4H9 on 39 c n c 11 0 CH3 CH ,"LI'X I 40 c l 5 L 5 iff 5H 41 C2H5 c 11 @C3H7 CH3 EXAMPLES 42-50 Following the procedure ofexample 20 but substituting the amine shown in column A for theethylam'me results in the production of the compounds of column B.

Column A Example R R., tihftyvii 123- j 42 H CH Following the procetlun9 example 8b hut substitut- 12 ing the aldehydes or ketoncu ln wvn incolumn A for the 45 9; cj 5 acetone results in the production of thecompounds of 4c, CH; 2 5 column B. 47 zt 1 tI T 48 (HH, t n 49 CH, (RH;50 (2H5 (3H7 Column A Column B EXAMPLES l62 9 0 oc H Following theprocedure of example 8a but substituting the hydrazines shown in columnA for the hydrazine 10 2 5 hydrate results in the production of thecompounds of column B. l

R NN=C 9 Column A Column B H \R 7 H NN o 2 5 8 11 Example R R H C N l l63 H CH b4 3O 3 ILN R 64 H c u H 65 H C H 66 H C H Example R R 67 2 5 568 CH C H 51 C H 5 0 69 on c n.

2 C H 5 3 7 H 70 n 53 H 71 o o 54 O H 72 CH 55 C H c 5 73 2 5 56 7 7 74C l-I 57 CH C H 3 2 5 75 C H 58 CH C H 59 CH C H CH EXAMPLE 76 61 C Hl-Butyl-4-ethylarnino-6-methyl-lH-imidazo[4,5-

clpyridine-7-carboxylic acid ethyl ester hydrochloride.

(,0 By treating the l-butyl-4-ethylamino-fi-methyl-lH- EXAMPLE 77l-Ethyl-4-hydrazino-6-methyl-imidazo 4,5-c lpyridine- 7-carboxylic acidethyl ester hydrochloride.

By treating the l-ethyl-4-hydrazino-6-methyl-lH-imidazo-[4,5-clpyridine-7-carboxylic acid ethyl ester of example 8a withan equivalent amount of HCl, the l-ethyl-4-hydrazino-6-methyllH-imidazo[4,5- c]pyridine-7-carboxylic acid ethyl ester hydrochloride isobtained.

EXAMPLE 78 1-Ethy1-6-methyl-4-l 2-( l-methylethylidene )hydrazino]- lH-imidazol 4,5-c lpyridine-7- carboxylic acid ethyl ester hydrochloride.

By treating the l-ethyl-4-[2-(l-methyl-ethylidene)- hydrazino1-lH-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester of example 8bwith an equivalent amount of HCl, the l-ethyl-6-methyl-4-[2-(l-methylethylidene )hydrazino1-l H-imidazo[4,5-clpyridine-7- carboxylicacid ethyl ester hydrochloride is obtained.

What is claimed is:

l. A compound of the formula wherein R and R are independently selectedfrom the group consisting of hydrogen and lower alkyl, R,, R,, and R areindependently selected from the group consisting of hydrogen, loweralkyl, and phenyl, and R, is selected from the group consisting of loweralkyl and phenyl; R, is selected from the group consisting of hydrogen,lower alkyl, and phenyl; and pharmaceutically acceptable acid additionsalts thereof.

2. A compound as in claim 1 wherein R, R,, R, and R, are independentlyselected from the group consisting of hydrogen and lower alkyl of l to 4carbons; and R is lower alkoxy of l to 4 carbons.

3. A compound as in claim 2 wherein R is ethyl; R, is ethyl; R ishydrogen; R is ethoxy; and R, is methyl.

4. A compound as in claim 1 wherein R, R,, R and R, are independentlyselected from the group consisting of hydrogen and lower alkyl of l to 4carbons; and R3 is wherein R and R are independently selected from thegroup consisting of hydrogen and lower alkyl of l to 4 carbons.

S. A compound as in claim 4 wherein R is ethyl; R, is selected from thegroup consisting of ethyl and butyl; R is selected from the groupconsisting of hydrogen and methyl; and R, is methyl.

6. A compound as in claim 5 wherein R, is butyl; R is hydrogen; and Rand R are both hydrogen.

7. A compound as in claim 5 wherein R, is butyl; R, is hydrogen; R ishydrogen; and R is ethyl.

8. A compound as in claim 5 wherein R, is ethyl; R is hydrogen; R ishydrogen; and R, is ethyl.

9. A compound as in claim 5 wherein R, is ethyl; R is methyl; R ishydrogen; and R is ethyl.

10. A compound as in claim 5 wherein R, is ethyl; R is methyl; R ishydrogen; and R is butyl.

11. A compound as in claim 5 wherein R, is ethyl; R is hydrogen; R ishydrogen; and R is butyl.

12. A compound as in claim 1 wherein R, R,, R and R, are independentlyselected from the group consisting of hydrogen and lower alkyl of l to 4carbons; and R3 is l a s wherein R is hydrogen and R is selected fromthe group consisting of hydrogen and lower alkyl of l to 4 carbons.

13. A compound as in claim 12 wherein R is ethyl; R is ethyl; R ishydrogen; R is methyl; and R, and R are both hydrogen.

14. A compound as in claim I wherein R, R,, R, and R are independentlyselected from the group consisting of hydrogen and lower alkyl of l to 4carbons; and R is wherein R and R, are each lower alkyl of l to 4carbons.

15. A compound as in claim 14 wherein R is ethyl; R, is ethyl; R, ishydrogen; R is methyl; and R,; and R, are both methyl.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 3,891,660

DATED June 24 1975 INVENTOHS) i T. Denzel et al it is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown DEIDWL Col. 3, structure VIIIshould read as follows:

H R H COOR N Q Col. 5, structure XIII should read as follows:

Col. 8, in the title of example 3(a) "ethylamino-l2methyl- 5-nitror"should read ethylamino-2-methyl5nitro.

Col

Col. 10, line 23, "andn" should read -and-.

Col. 10, the structure (Ia) should read as follows:

O R, R r 4w; NVRZ I It 8, line 48, "nitropyridine" should read-nitropyridine- UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTION PATENT NO. I 3,891 ,660 Page 2 DATED 5 24/75 INVENTOR(S) T.Denzel et al.

It is ceriified that EHO! app-ems in 'zhe HIIOJU-TIILIHIIIEGG paieni andiildi said L-adms Paten? are hereby corrected as shown below:

Example 12 should read across as follows:

Signed and Sealed this sixteenth D a y Of September 1 9 75 [SEAL]Attest:

RUTH C. MASON C. MARSHALL DANN Alresring Officer (mnmlssmnor 0] Parentsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R, R1,R2 and R4 are independently selected from the group consisting ofhydrogen and lower alkyl of 1 to 4 carbons; and R3 is lower alkoxy of 1to 4 carbons.
 3. A compound as in claim 2 wherein R is ethyl; R1 isethyl; R2 is hydrogen; R3 is ethoxy; and R4 is methyl.
 4. A compound asin claim 1 wherein R, R1, R2 and R4 are independently selected from thegroup consisting of hydrogen and lower alkyl of 1 to 4 carbons; and R3is
 5. A compound as in claim 4 wherein R is ethyl; R1 is selected fromthe group consisting of ethyl and butyl; R2 is selected from the groupconsisting of hydrogen and methyl; and R4 is methyl.
 6. A compound as inclaim 5 wherein R1 is butyl; R2 is hydrogen; and R5 and R6 are bothhydrogen.
 7. A compound as in claim 5 wherein R1 is butyl; R2 ishydrogen; R5 is hydrogen; and R6 is ethyl.
 8. A compound as in claim 5wherein R1 is ethyl; R2 is hydrogen; R5 is hydrogen; and R6 is ethyl. 9.A compounD as in claim 5 wherein R1 is ethyl; R2 is methyl; R5 ishydrogen; and R6 is ethyl.
 10. A compound as in claim 5 wherein R1 isethyl; R2 is methyl; R5 is hydrogen; and R6 is butyl.
 11. A compound asin claim 5 wherein R1 is ethyl; R2 is hydrogen; R5 is hydrogen; and R6is butyl.
 12. A compound as in claim 1 wherein R, R1, R2, and R4 areindependently selected from the group consisting of hydrogen and loweralkyl of 1 to 4 carbons; and R3 is
 13. A compound as in claim 12 whereinR is ethyl; R1 is ethyl; R2 is hydrogen; R4 is methyl; and R7 and R8 areboth hydrogen.
 14. A compound as in claim 1 wherein R, R1, R2 and R4 areindependently selected from the group consisting of hydrogen and loweralkyl of 1 to 4 carbons; and R3 is
 15. A compound as in claim 14 whereinR is ethyl; R1 is ethyl; R2 is hydrogen; R4 is methyl; and R9 and R10are both methyl.